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Friendship is critical for individuals' well-being, but recent efforts to characterize Americans' friendship have suggested that these relationships are in peril. The present study is a report on the methods and results of three surveys from the American Friendship Project (AFP). The goal of the AFP is to be the most accurate and most complete account of American friendship as well as its health and change over time. The AFP reports on five critical facets of social health as it relates to friendship: 1) the structural factors of friendship (e.g., who are they, how many); 2) friendship quality (e.g., satisfaction, closeness); 3) social support from friends; 4) the quantity of online and offline communication; and 5) well-being (e.g., life satisfaction, loneliness, connection). Data was collected from two national samples of American adults in 2022 and 2023 and from a large sample of college students across three universities in 2022. The key finding from this investigation is, compared to the discouraging results of other recent surveys, Americans reported having more friends and fewer were friendless. AFP results also suggest that face-to-face (FtF) meetings among friends are quite common, as are telephone calls and text messaging. College student and adult samples reported very similar attitudes and experiences with friendship overall, but students were more likely to meet friends at school and to keep them for a shorter length of time. Another key finding is Americans long for greater closeness with friends; though over 75% were satisfied with the number of friends they had, over 40% felt they were not as close to their friends as they would like. Overall, the AFP is a rich source of data that can be used to answer a multitude of questions about friendship and its connection to well-being., Competing Interests: No authors have competing interests., (Copyright: © 2024 Pennington et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Unplanned pregnancies are associated with increased risks. Despite this, they are currently not routinely detected during antenatal care. This study evaluates the implementation of the London Measure of Unplanned Pregnancy (LMUP) - a validated measure of pregnancy planning - into antenatal care at University College London Hospital, Homerton Hospital, and St Thomas' Hospital, England, 2019-2023., Methods: We conducted a mixed methods evaluation of the pilot. Uptake and acceptability were measured using anonymized data with non-completion of the LMUP as a proxy measure of acceptability overall. We conducted focus groups with midwives, and one-to-one interviews with women, to explore their thoughts of asking, or being asked the LMUP, which we analyzed with a Framework Analysis., Results: Asking the LMUP at antenatal appointments is feasible and acceptable to women and midwives, and the LMUP performed as expected. Advantages of asking the LMUP, highlighted by participants, include providing additional support and personalizing care. Midwives' concerns about judgment were unsubstantiated; women with unplanned pregnancies valued such discussions., Conclusions: These findings support the implementation of the LMUP in routine antenatal care and show how it can provide valuable insights into the circumstances of women's pregnancies. This can be used to help midwives personalize care, and potentially reduce adverse outcomes and subsequent unplanned pregnancy. Integration of the LMUP into the Maternity Services Data Set will establish national data collection of a validated measure of unplanned pregnancy and enable analysis of the prevalence, factors, and implications of unplanned pregnancies across subpopulations and over time to inform implementation., Competing Interests: The authors have each completed and submitted an ICMJE form for Disclosure of Potential Conflicts of Interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work. J. Hall and C. Stewart report that Dama Health made payments to their institution for research consultancy relating to contraception research. H. Duncan reports that she has a leadership/fiduciary role in the coalition of academic experts and public health professionals of the UK Preconception Partnership and in the Ministerial taskforce for supporting with evidence and data from a civil service perspective of the Maternity Disparities Taskforce. She also reports substantive employment in The Office for Health Improvement and Disparities at the Department of Health and Social Care. J. Hall reports that travel and accommodation costs to attend an Annual Scientific Meeting in June 2023, were covered by the Faculty of Sexual and Reproductive Health; the NIHR Advanced Fellowship funds her salary and this research; she participates in the Data Safety Monitoring Board of ALERT; and she is a member without payment of the NHS England Maternity Transformation Programme, Public Health and Prevention Advisory Group and the Faculty of Sexual and Reproductive Health Research Group. H. Lovell reports that she has received a personal research development award from the NIHR Doctoral Clinical Academic Research Fellowship (Grant number 302860)., (© 2024 Hall J.A. et al.)

findings are presented from an investigation to improve understanding of the environmental risks associated with developing an unconventional-hydrocarbons industry in the UK. The EQUIPT4RISK project, funded by UK Research Councils, focused on investigations around Preston New Road (PNR), Fylde, Lancashire, and Kirby Misperton Site A (KMA), North Yorkshire, where operator licences to explore for shale gas by hydraulic fracturing (HF) were issued in 2016, although exploration only took place at PNR. EQUIPT4RISK considered atmospheric (greenhouse gases, air quality), water (groundwater quality) and solid-earth (seismicity) compartments to characterise and model local conditions and environmental responses to HF activities. Risk assessment was based on the source-pathway-receptor approach. Baseline monitoring of air around the two sites characterised the variability with meteorological conditions, and isotopic signatures were able to discriminate biogenic methane (cattle) from thermogenic (natural-gas) sources. Monitoring of a post-HF nitrogen-lift (well-cleaning) operation at PNR detected the release of atmospheric emissions of methane (4.2 ± 1.4 t CH 4 ). Groundwater monitoring around KMA identified high baseline methane concentrations and detected ethane and propane at some locations. Dissolved methane was inferred from stable-isotopic evidence as overwhelmingly of biogenic origin. Groundwater-quality monitoring around PNR found no evidence of HF-induced impacts. Two approaches for modelling induced seismicity and associated seismic risk were developed using observations of seismicity and operational parameters from PNR in 2018 and 2019. Novel methodologies developed for monitoring include use of machine learning to identify fugitive atmospheric methane, Bayesian statistics to assess changes to groundwater quality, a seismicity forecasting model seeded by the HF-fluid injection rate and high-resolution monitoring of soil-gas methane. The project developed a risk-assessment framework, aligned with ISO 31000 risk-management principles, to assess the theoretical combined and cumulative environmental risks from operations over time. This demonstrated the spatial and temporal evolution of risk profiles: seismic and atmospheric impacts from the shale-gas operations are modelled to be localised and short-lived, while risk to groundwater quality is longer-term., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: For health services to help people plan for or prevent pregnancy, health professionals need an acceptable way to identify individuals' preferences., Objective: To assess women's views on the acceptability of specific questions about pregnancy preferences when asked by health professionals in a variety of primary care contexts., Methods: One-to-one in-depth interviews with 13 women aged 18-48 from across the UK, involving role-play scenarios and ranking exercises. Interviews covered a range of settings and health professionals, different question wording, and ways of asking (in person or digitally). We conducted a thematic Framework Analysis, focussing on themes relating to feelings and preferences., Results: Women were generally open to being asked about pregnancy preferences if they understood the rationale, it was asked in a relevant context, such as in women's health-related consultations, and there was follow-up. After signposting, an open question, such as 'How would you feel about having a baby in the next year?' was preferred in a face-to-face context as it enabled discussion. While some women valued a face-to-face discussion with a health professional, for others the privacy and convenience of a digital option was preferred; methods should be tailored to the target population., Conclusion: Discussion of pregnancy preferences via a range of formats is acceptable to, and valued by, women in the UK across a range of primary care settings. Acceptability to health professionals and feasibility of implementation needs further exploration and would benefit from greater public awareness of the benefits of pregnancy planning., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R., Methods: Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL., Results: The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam 3 CSK 4 . Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1R WT/KO and CSF1R WT/E633K iMGL compared to their respective isogenic controls., Conclusions: We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities., (© 2024. The Author(s).)

Metformin restores the myelination potential of aged rat A2B5+ oligodendrocyte progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4+A2B5+) have a superior capacity to ensheath nanofibres compared to mature oligodendrocytes, with cells from paediatric sources exceeding adults. In this study, we assessed the effects of metformin on ensheathment capacity of human adult and paediatric progenitors and mature oligodendrocytes and related differences to transcriptional changes. A2B5+ progenitors and mature cells, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofibre plates over 2 weeks. Metformin (10 µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature oligodendrocytes. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by paediatric cells. Metformin marginally increased cell death in paediatric progenitors. Metformin-induced changes in gene expression are distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in the process of outgrowth and promoting lipid biosynthesis. Paediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development and synaptic transmission. Metformin-induced AMP-activated protein kinase activation in all cell types; AMP-activated protein kinase inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage-related differences in human oligodendroglia lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate in vivo ., Competing Interests: There are no conflicts of interest to report., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: We assessed contraceptive use changes during the second lockdown due to COVID-19 in Brazil and their associated factors., Study Design: This was a longitudinal web-based study in which 725 non-pregnant Brazilian women aged 18 to 49 completed an online structured survey about their contraceptive practices in two rounds in 2021. Multivariate multinomial logistic regression was used to analyze factors associated with contraceptive use changes during COVID-19., Results: Sixty percent reported they changed their contraceptive use during COVID-19, especially starting to use a method or switching to a more effective one (32%). In adjusted analysis, women who were ambivalent about a future pregnancy were more likely to switch to a more effective method (adjusted odds ratio [aOR] 2.33, 95% CI 1.42-3.83) and to stop using contraceptive (aOR 3.64, 95% CI 1.91-6.91). Women with a partner were less likely to switch to a more effective method (aOR 0.61, 95% CI 0.39-0.93) and to stop using contraceptive (aOR 0.53, 95% CI 0.31-0.93), but more likely to switch to a less effective method (aOR 2.25, 95% CI 1.16-4.34). Age was also associated with contraceptive use changes., Conclusions: Contraceptive use among Brazilian women during COVID-19 depended on their age and partnership status. During the period of the highest peak in the number of cases and deaths in the country, ambivalence towards a future pregnancy increased changes in contraceptive use., Implications: Contraceptive changes were observed during a two-wave web-survey in Brazil depending on women's age and partnership status. Ambivalence towards a future pregnancy increased changes in contraceptive use and should be considered in future studies regarding sexual and reproductive health and COVID-19 as well as in family planning program implementation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions., (© 2024. The Author(s).)

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1β secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 × 10-21), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson's disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To offer a critique of empathy concept usage in healthcare and medical education research., Methods: Analysis of current usage and suggestions for authors and researchers., Results: Empathy is often undefined or inconsistently defined, and "empathy" as represented in research covers an unmanageably wide and varied range of intentions, attitudes, emotions, and behaviors. The ubiquitous use of "empathy" as a vague and often undefined umbrella term hinders comprehension and, therefore, scientific progress. Patients are rarely asked directly about empathy; instead, measures of so-called perceived empathy contain descriptive items that could as well be called quality of care, patient-centeredness, or patient satisfaction., Conclusions: Although "empathy" in medical care is widely valued by researchers, educators, and practitioners, the empathy concept as used in the published literature is overused and unclear, and potentially damaging to scholarship, medical education, and ultimately healthcare. The vague term empathy should be replaced as much as possible with concrete descriptions of what is actually measured, experimentally manipulated, or taught., Practice Implications: Identifying patients' own empathy definitions will improve medical education and medical care through clarifying what clinical behaviors will best fulfill patients' needs and desires. This approach allows for greater specificity and personalized care delivery., Competing Interests: Declaration of Competing Interest There are no competing (conflicting) interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The term "empathic accuracy" has been applied to people's ability to infer the contents of other people's minds-that is, other people's varying feelings and/or thoughts over the course of a social interaction. However, despite the ease of intuitively linking this skill to competence in helping professions such as counseling, the "empathic" prefix in its name may have contributed to overestimating its association with prosocial traits and behaviors. Accuracy in reading others' thoughts and feelings, like many other skills, can be used toward prosocial-but also malevolent or morally neutral-ends. Prosocial intentions can direct attention towards other people's thoughts and feelings, which may, in turn, increase accuracy in inferring those thoughts and feelings, but attention to others' thoughts and feelings does not necessarily heighten prosocial intentions, let alone outcomes.

Importance: An understanding of the processes that contribute to the emergence of pathogens from environmental reservoirs is critical as changing climate precipitates pathogen evolution and population expansion. Phylogeographic analysis of Vibrio parahaemolyticus hosts combined with the analysis of their Inoviridae phage resolved ambiguities of diversification dynamics which preceded successful Atlantic invasion by the epidemiologically predominant ST36 lineage. It has been established experimentally that filamentous phage can limit host recombination, but here, we show that phage loss is linked to rapid bacterial host diversification during epidemic spread in natural ecosystems alluding to a potential role for ubiquitous inoviruses in the adaptability of pathogens. This work paves the way for functional analyses to define the contribution of inoviruses in the evolutionary dynamics of environmentally transmitted pathogens., Competing Interests: The authors declare no conflict of interest.

Objective: In drug-resistant temporal lobe epilepsy (TLE), it is not well-established in how far surgery should target morphological anomalies to achieve seizure freedom. Here, we assessed interactions between structural brain compromise and surgery to identify region-specific predictors of seizure outcome., Methods: We obtained pre- and post-operative 3D T1-weighted MRI in 55 TLE patients who underwent selective amygdalo-hippocampectomy (SAH) or anterior temporal lobectomy (ATL) and 40 age and sex-matched healthy subjects. We measured surface-based morphological alterations of the mesiotemporal lobe structures (hippocampus, amygdala, entorhinal and piriform cortices), the neocortex and the thalamus on both pre- and post-operative MRI. Using precise co-registration, in each patient we mapped the surgical cavity onto the MRI acquired before surgery, thereby quantifying the amount of pathological tissue resected; these features, together with the preoperative morphometric data, served as input to a supervised classification algorithm for postsurgical outcome prediction., Results: On pre-operative MRI, patients who became seizure-free (TLE-SF) presented with severe ipsilateral amygdalar and hippocampal atrophy, while not seizure-free patients (TLE-NSF) displayed amygdalar hypertrophy. Stratifying patients based on the surgical approach, post-operative MRI showed similar patterns of mesiotemporal and thalamic changes, but divergent neocortical thinning affecting the parieto-temporo-occipital regions following ATL and the frontal lobes after SAH. Irrespective of the surgical approach, hippocampal atrophy on pre-operative MRI and its extent of resection were the most predictive features of seizure-freedom in 89% of patients (selected 100% across validations)., Significance: Our study indicates a critical role of the extent of resection of MRI-derived hippocampal morphological anomalies on seizure outcome. Precise pre-operative quantification of the mesiotemporal lobe provides non-invasive prognostics for individualized surgery., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The fixation of periprosthetic fractures remains challenging and controversial. It is important to achieve consensus opinions regarding the management of stable periprosthetic fractures with internal fixation. Key strategies to optimize surgical decision making and fixation and manage complications following these difficult injuries are addressed.

The management of periprosthetic fractures with unstable prosthetic implants is a challenging and commonly encountered problem. It is important to address the many current issues and controversies regarding the treatment of periprosthetic fractures with revision total joint arthroplasty. Key strategies to optimize surgical decision making around the use of arthroplasty and management of complications following these complex injuries will be addressed.

Progranulin is a secreted pro-protein that has anti-inflammatory and neurotrophic effects and is necessary for maintaining lysosomal function. Mutations in progranulin (GRN) are a major cause of frontotemporal dementia. Most pathogenic GRN mutations cause progranulin haploinsufficiency, so boosting progranulin levels is a promising therapeutic strategy. Progranulin is constitutively secreted, then taken up and trafficked to lysosomes. Before being taken up from the extracellular space, progranulin interacts with receptors that may mediate anti-inflammatory and growth factor-like effects. Modifying progranulin trafficking is a viable approach to boosting progranulin, but progranulin secretion and uptake by cells in the brain is poorly understood and may involve distinct mechanisms from other parts of the body. Understanding the cell types and processes that regulate extracellular progranulin in the brain could provide insight into progranulin's mechanism of action and inform design of progranulin-boosting therapies. To address this question we used microdialysis to measure progranulin in interstitial fluid (ISF) of mouse medial prefrontal cortex (mPFC). Grn +/- mice had approximately 50% lower ISF progranulin than wild-type mice, matching the reduction of progranulin in cortical tissue. Fluorescent in situ hybridization and immunofluorescence confirmed that microglia and neurons are the major progranulin-expressing cell types in the mPFC. Studies of conditional microglial (Mg-KO) and neuronal (N-KO) Grn knockout mice revealed that loss of progranulin from either cell type results in approximately 50% reduction in ISF progranulin. LPS injection (i.p.) produced an acute increase in ISF progranulin in mPFC. Depolarizing cells with KCl increased ISF progranulin, but this response was not altered in N-KO mice, indicating progranulin secretion by non-neuronal cells. Increasing neuronal activity with picrotoxin did not increase ISF progranulin. These data indicate that microglia and neurons are the source of most ISF progranulin in mPFC, with microglia likely secreting more progranulin per cell than neurons. The acute increase in ISF progranulin after LPS treatment is consistent with a role for extracellular progranulin in regulating inflammation, and may have been driven by microglia or peripheral immune cells. Finally, these data indicate that mPFC neurons engage in constitutive progranulin secretion that is not acutely changed by neuronal activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment., (© 2023. Springer Nature Limited.)

Objective: To determine the completion rate for the London Measure of Unplanned Pregnancy (LMUP), a psychometrically validated measure of a woman's intention with regard to a current or recent pregnancy, during booking visits at two metropolitan antenatal care clinics; to identify socio-demographic characteristics associated with unplanned pregnancy., Design, Setting, Participants: Retrospective cohort study; analysis of LMUP data for women attending antenatal care booking consultations as public patients in the Sydney Local Health District, 31 December 2019 - 30 November 2020., Main Outcome Measures: Proportions of women with LMUP scores indicating unplanned (0-9) or planned pregnancies (10-12); associations between planned pregnancy and socio-demographic characteristics, crude and adjusted for age, parity, and socio-economic status (Index of Relative Socioeconomic Disadvantage)., Results: Of 4993 women with antenatal care bookings, the LMUP was completed by 2385 (47.8%; 1142 of 3564 women at the tertiary referral hospital [32.0%], 1118 of 1160 at the secondary hospital [96.3%]). Planned pregnancies were indicated by the total LMUP scores of 1684 women (70.6%); 1290 women (59.1%) reported no health actions in preparation for pregnancy. In multivariable analyses, planned pregnancies were more likely in all age groups than for women aged 24 years or younger (30-34 years: adjusted odds ratio [aOR], 2.54; 95% confidence interval [CI], 1.76-3.66; 35-39 years: aOR, 2.91; 95% CI, 1.95-4.33). The likelihood of planned pregnancy declined with increasing parity (v no previous births: three previous births: aOR, 0.25; 95% CI, 0.16-0.40; four or more previous births: aOR, 0.10; 95% CI, 0.05-0.19)., Conclusion: Seven in ten women who completed the LMUP had planned their pregnancies, but fewer than half had undertaken health-related actions prior to conceiving. Higher parity was associated with unplanned pregnancy, indicating the importance of postpartum contraception advice. Overcoming barriers to implementing the LMUP more widely would enhance preconception health monitoring., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Selenium (Se) agronomic biofortification of plants is effective for alleviating Se deficiencies in human and livestock populations. Less is known about how higher selenate amendment rates, or how foliar compared with granular selenate amendments affect forage Se concentrations. Therefore, we compared the effects of a higher sodium selenate foliar amendment rate (900 vs. 90 g Se ha -1 ), and two selenate amendment methods (liquid foliar sodium selenate vs. granular slow-release Selcote Ultra ® at 0, 45, and 90 g Se ha -1 ) on Se concentrations and Se species in forages across Oregon. The 10 × amendment rate (900 g Se ha -1 ) resulted in 6.4 × higher forage Se concentrations in the first cut (49.19 vs. 7.61 mg Se kg -1 plant DM, respectively) compared with the 90 g ha -1 amendment rate, indicating that forages can tolerate higher selenate amendment rates. Most Se was incorporated as SeMet (75%) in the harvested portion of the forage (37 mg Se kg -1 forage DM of the first cut) and only a limited amount was stored in the selenate reserve pool in the leaves (~ 5 mg Se kg -1 forage DM). Higher application rates of selenate amendment increased forage Se concentrations in first and second cuts, but carry over in subsequent years was negligible. Application of foliar selenate vs. granular Selcote Ultra ® amendments, between 0 and 90 g Se ha -1 , both resulted in a linear, dose-dependent increase in forage Se concentration. Amendments differed in their Se incorporation pattern (Se%), in that, first cut forage Se concentrations were higher with foliar selenate amendment and second, third, and residual (following spring) cut forage Se concentrations were higher with granular Selcote Ultra® amendment. Given the linear relationship between forage Se concentrations and whole-blood Se concentrations in livestock consuming Se-biofortified forage, we conclude that targeted grazing or other forage feeding strategies will allow producers to adapt to either selenate-amendment form., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A longstanding gap in the reproductive health field has been the availability of a screening instrument that can reliably predict a person's likelihood of becoming pregnant. The Desire to Avoid Pregnancy Scale is a new measure; understanding its sensitivity and specificity as a screening tool for pregnancy as well as its predictive ability and how this varies by socio-demographic factors is important to inform its implementation., Methods: This analysis was conducted on a cohort of 994 non-pregnant participants recruited in October 2018 and followed up for one year. The cohort was recruited using social media as well as advertisements in a university, school, abortion clinic and outreach sexual health service. Almost 90% of eligible participants completed follow-up at 12 months; those lost to follow-up were not significantly different on key socio-demographic factors. We used baseline DAP score and a binary variable of whether participants experienced pregnancy during the study to assess the sensitivity, specificity, area under the ROC curve (AUROC) and positive and negative predictive values (PPV and NPV) of the DAP at a range of cut-points. We also examined how the predictive ability of the DAP varied according to socio-demographic factors and by the time frame considered (e.g., pregnancy within 3, 6, 9 and 12 months)., Results: At a cut-point of 2 on the 0-4 range of the DAP scale, the DAP had a sensitivity of 0.78, a specificity of 0.81 and an excellent AUROC of 0.87. In this sample the cumulative incidence of pregnancy was 16% (95%CI 13%, 18%) making the PPV 43% and the NPV 95% at this cut-point. The DAP score was the factor most strongly associated with pregnancy, even after age and number of children were taken into account. The association between baseline DAP score and pregnancy did not differ across time frames., Conclusions: This is the first study to assess the DAP scale as a screening tool and shows that its predictive ability is superior to the limited pre-existing pregnancy prediction tools. Based on our findings, the DAP could be used with a cut-point selected according to the purpose., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters Ag-specific Ab and cellular immune responses to oral and parenteral vaccination in mice. Oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine expressing chicken egg OVA (Salmonella-OVA) induced the accumulation of activated, OVA-specific T effector cells rather than OVA-specific regulatory T cells in the GALT. Intestinal helminth infection significantly reduced Th1-skewed Ab responses to oral vaccination with Salmonella-OVA. Activated, adoptively transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes of vaccinated mice, regardless of their helminth infection status. However, helminth infection increased the frequencies of adoptively transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the mesenteric lymph node. Ab responses to the oral Salmonella-OVA vaccine were reduced in helminth-free mice adoptively transferred with OVA-specific CD4+ T cells harvested from mice with intestinal helminth infection. Intestinal helminth infection also significantly reduced Th2-skewed Ab responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest that vaccine-specific CD4+ T cells induced in the context of helminth infection retain durable immunomodulatory properties and may promote blunted Ab responses to vaccination. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Reproductive autonomy-control over outcomes including contraceptive use and childbearing-is a human right and vital to women's empowerment. Those whose reproductive autonomy is threatened by the structures and relationships in their lives are at risk of coercion and unplanned pregnancy and could benefit from additional services. The Reproductive Autonomy Scale (RAS) was developed in the USA to assess women's reproductive autonomy; this study evaluates the RAS for use in the UK., Methods: After testing, the RAS was incorporated into an online survey of women of reproductive age. Those who were sexually active were asked to complete the RAS, which was evaluated according to classical test theory. Reliability was assessed via internal consistency and a 3-month test-retest. Construct validity was assessed using hypothesis testing and confirmatory factor analysis., Results: For 826 women the RAS was highly acceptable, with a response rate of >97.7%. Almost the whole range of reproductive autonomy scores were captured. Internal consistency was good, with a Cronbach's α of 0.75. Test-retest reliability was fair-good with an intraclass correlation coefficient of 0.67. Construct validity analysis found the scale to be valid based on our hypothesis that among women who want to avoid pregnancy, those with higher reproductive autonomy will be more likely to use contraception. The three-factor structure of the scale was confirmed on confirmatory factor analysis., Conclusion: The RAS is valid and reliable for use in the UK. This tool holds potential utility across research, clinical practice, health interventions and policy development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Clinicians and women of reproductive age would benefit from a reliable way to identify who is likely to become pregnant in the next year, in order to direct health advice. The 14-item Desire to Avoid Pregnancy (DAP) scale is predictive of pregnancy; this paper compares it with other ways of assessing pregnancy preferences to shortlist options for clinical implementation., Methods: A cohort of 994 UK women of reproductive age completed the DAP and other questions about pregnancy preferences, including the Attitude towards Potential Pregnancy Scale (APPS), at baseline and reported on pregnancies quarterly for a year. For each question, DAP item and combinations of DAP items, we examined the predictive ability, sensitivity, specificity, area under the receiver operating curve (AUROC), and positive and negative predictive values., Results: The AUROCs and predictive ability of the APPS and DAP single items were weaker than the full DAP, though all except one had acceptable AUROCs (>0.7). The most predictive individual DAP item was 'It would be a good thing for me if I became pregnant in the next 3 months', where women who strongly agreed had a 66.7% chance of pregnancy within 12 months and the AUROC was acceptable (0.77)., Conclusion: We recommend exploring the acceptability to women and healthcare professionals of asking a single DAP item ('It would be a good thing for me if I became pregnant in the next 3 months'), possibly in combination with additional DAP items. This will help to guide service provision to support reproductive preferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Aggregates of conjugated organic molecules (i.e., dyes) may exhibit relatively large one- and two-exciton interaction energies, which has motivated theoretical studies on their potential use in quantum information science (QIS). In practice, one way of realizing large one- and two-exciton interaction energies is by maximizing the transition dipole moment (μ) and difference static dipole moment (Δ d ) of the constituent dyes. In this work, we characterized the electronic structure and excited-state dynamics of monomers and aggregates of four asymmetric polymethine dyes templated via DNA. Using steady-state and time-resolved absorption and fluorescence spectroscopy along with quantum-chemical calculations, we found the asymmetric polymethine dye monomers exhibited a large μ, an appreciable Δ d , and a long excited-state lifetime (τ p ). We formed dimers of all four dyes and observed that one dye, Dy 754, displayed the strongest propensity for aggregation and exciton delocalization. Motivated by these results, we undertook a more comprehensive survey of Dy 754 dimer and tetramer aggregates using steady-state absorption and circular dichroism spectroscopy. Modeling these spectra revealed an appreciable excitonic hopping parameter ( J ). Lastly, we used femtosecond transient absorption spectroscopy to characterize τ p of the dimer and tetramer, which we observed to be exceedingly short. This work revealed that asymmetric polymethine dyes exhibited μ, Δ d , monomer τ p , and J values promising for QIS; however, further work is needed to overcome excited-state quenching and achieve long aggregate τ p .

Background: Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis., Method: In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope., Results: We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states., Conclusion: In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease., (© 2023. The Author(s).)

Bacterial blight resistance gene B 5 has received little attention since it was first described in 1950. A near-isogenic line (NIL) of Gossypium hirsutum cotton, Ac B 5 , was generated in an otherwise bacterial-blight-susceptible 'Acala 44' background. The introgressed locus B 5 in Ac B 5 conferred strong and broad-spectrum resistance to bacterial blight. Segregation patterns of test crosses under Oklahoma field conditions indicated that Ac B 5 is likely homozygous for resistance at two loci with partial dominance gene action. In controlled-environment conditions, two of the four copies of B 5 were required for effective resistance. Contrary to expectations of gene-for-gene theory, Ac B 5 conferred high resistance toward isogenic strains of Xanthomonas citri subsp. malvacearum carrying cloned avirulence genes avrB4 , avrb7 , avrBIn , avrB101 , and avrB102 , respectively, and weaker resistance toward the strain carrying cloned avrb6 . The hypothesis that each B gene, in the absence of a polygenic complex, triggers sesquiterpenoid phytoalexin production was tested by measurement of cadalene and lacinilene phytoalexins during resistant responses in five NILs carrying different B genes, four other lines carrying multiple resistance genes, as well as susceptible Ac44E. Phytoalexin production was an obvious, but variable, response in all nine resistant lines. Ac B 5 accumulated an order of magnitude more of all four phytoalexins than any of the other resistant NILs. Its total levels were comparable to those detected in OK1.2, a highly resistant line that possesses several B genes in a polygenic background., Competing Interests: The author(s) declare no conflict of interest.

Efforts to understand microglia function in health and diseases have been hindered by the lack of culture models that recapitulate in situ cellular properties. In recent years, the use of serum-free media with brain-derived growth factors (colony stimulating factor 1 receptor [CSF1R] ligands and TGF-β1/2) have been favored for the maintenance of rodent microglia as they promote morphological features observed in situ. Here we study the functional and transcriptomic impacts of such media on human microglia (hMGL). Media formulation had little impact on microglia transcriptome assessed by RNA sequencing which was sufficient to significantly alter microglia capacity to phagocytose myelin debris and to elicit an inflammatory response to lipopolysaccharide. When compared to immediately ex vivo microglia from the same donors, the addition of fetal bovine serum to culture media, but not growth factors, was found to aid in the maintenance of key signature genes including those involved in phagocytic processes. A phenotypic shift characterized by CSF1R downregulation in culture correlated with a lack of reliance on CSF1R signaling for survival. Consequently, no improvement in cell survival was observed following culture supplementation with CSF1R ligands. Our study provides better understanding of hMGL in culture, with observations that diverge from those previously made in rodent microglia., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)

Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick's disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick's disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD subtypes., (© 2023. The Author(s).)

Objectives: To better understand the relationships among treatment, pain, and physical function (PF)., Methods: Data were collected from 2 published randomized clinical trials of osteoarthritis patients who received tanezumab or a placebo. PF was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) PF domain. Pain (WOMAC pain domain) was a mediator of the effect of treatment on PF. A set of mediation models were investigated. Variables were treatment (tanezumab vs placebo), WOMAC pain domain, and WOMAC PF domain. Cross-sectional mediation models were assessed separately at different weeks. Longitudinal mediation models used data from all weeks simultaneously. Results could identify a steady-state period., Results: The cross-sectional and longitudinal mediation models showed a stable indirect effect of treatment through the pain on PF across time, indicating that a pseudo-steady-state model was appropriate. Therefore, the longitudinal steady-state mediation models were used with all available data assuming relationships among variables in the model being the same at all time points; results showed that the indirect effect of the treatment on PF was 77.8% in study 1 (NCT02697773) and 74.1% in study 2 (NCT02709486), both P <0.0001, whereas the direct effect was 22.2% for study 1 ( P = 0.0003) and 25.9% for study 2 ( P = 0.0019)., Discussion: At least 75% of the treatment effect of tanezumab on physical functioning can be explained by the improvements in pain. However, tanezumab had an additional effect on physical functioning (~25%) that, was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Low selenium (Se) concentrations in soils and plants pose a health risk for ruminants consuming locally-grown forages. Previous studies have shown that Se concentrations in forages can be increased using soil-applied selenate amendments. However, the effects of foliar selenate amendments applied with traditional nitrogen-phosphorus-potassium-sulfur (NPKS) fertilizers on forage yields, and nutrient contents, and agronomic efficiencies are unknown., Methods: Using a split plot design, we determined the effects of springtime sodium selenate foliar amendment rates (0, 45, and 90 g Se ha -1 ) and NPKS application (none, NPK for grasses/PK for alfalfa, and NPKS/PKS fertilization at amounts adapted to meet local forage and soil requirements) on forage growth and N, S, and Se concentrations, yields, and agronomic efficiencies. This 2-year study was conducted across Oregon on four representative forage fields: orchardgrass ( Dactylis glomerata L.) in Terrebonne (central Oregon), grass-clover mixture in Roseburg (southwestern Oregon), and both grass mixture and alfalfa ( Medicago sativa L.) fields in Union (eastern Oregon)., Results: Grasses grew poorly and were low in N content without NPK fertilization. Fertilization with NPK/PK promoted forage growth, increased forage N concentrations, and had to be co-applied with S when plant available S was low. Without Se amendment, forage Se concentrations were low and further decreased with NPKS/PKS fertilization. Selenate amendment linearly increased forage Se concentration without adversely affecting forage yields, N and S concentrations, or N and S agronomic efficiencies., Discussion: Importantly, S fertilization did not interfere with Se uptake in Se amended plots. In conclusion, co-application of NPKS/PKS fertilizers and foliar sodium selenate in springtime is an effective strategy to increase forage total Se concentrations, while maintaining optimal growth and quality of Oregon forages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hall, Bobe, Filley, Bohle, Pirelli, Wang, Davis and Bañuelos.)

Framed by need to belong theory, this study considers the role of communication modality, geographic proximity, and the number of close relationship partners to predict life satisfaction and loneliness. A quota sample of American adults ( N  = 1,869) completed four name generation tasks to identify up to 16 alters, resulting in four alters per participant ( n  = 7,471). Participants reported the frequency with which they communicated with each alter in the past year in person and through eight interpersonal media. Results suggest that number of relationship partners and frequency of face-to-face interaction were robust predictors of life satisfaction and loneliness. Those living alone faced significant threats to well-being. Video chat and voice call frequency were also associated with greater life satisfaction. Mediation analyses showed voice call frequency was indirectly associated with less loneliness through greater relationship maintenance satisfaction, while lean media was indirectly associated with greater loneliness through relationship maintenance frustration., Supplementary Information: The online version contains supplementary material available at 10.1007/s10902-022-00581-8., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Despite evidence that reduction mammaplasty alleviates macromastia symptoms independent of resection weights, resection minimums are commonly used to grant insurance coverage. Multiple formulas have been published to predict resection weights, but very few have evaluated predictive performance relative to attaining common insurance minimums., Methods: This was a retrospective single-center review of 268 patients from 2007 to 2020. Multiple linear regression and exponential models were created to predict resection weights and attainment of the Schnur, 350-g, and 500-g minimums. Accuracy was compared against published Appel, Descamps, and Galveston equations. Body mass index subgroup analyses were performed., Results: The exponential model possessed the lowest resection weight prediction error overall (172.8 ± 211.5 g). All equations performed significantly better than surgeons in predicting attainment of the 500-g minimum. None performed better than the surgeons' predictive accuracy in attaining a 350-g minimum. Multiple linear regression and exponential models performed significantly better than surgeons in predicting attainment of the Schnur minimum. Only the exponential model performed significantly better than surgeons for both the Schnur (82% versus 71%; P < 0.01) and the 500-g minimums (89% versus 68%; P < 0.01). On body mass index subgroup analyses, all three minimums were biased in favor of obese women-the least egregious of these was the 350-g minimum., Conclusions: All minimums were biased against nonobese women. Our exponential model equation based on preoperative sternal notch-to-nipple and nipple-to-inframammary fold distances accurately predicts resection weights and improves on our surgeons' predictive accuracy in attaining the Schnur or 500-g minimums. This may prove useful in the preoperative setting to better counsel patients., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background: It is widely accepted that maternal healthcare is vital for improving maternal and neonatal mortality rates. Furthermore, the continuum of care-the integrated delivery of antenatal, delivery and postnatal care-has been shown to be particularly important. Sub-Saharan Africa has the highest neonatal and maternal mortality rates in the world; significant improvements in the provision and utilisation of the continuum are urgently needed, therefore the barriers preventing access need to be better understood. This study aimed to identify key factors associated with the utilisation of maternal healthcare, in the Mchinji District of Malawi., Methods: 4,244 pregnant women from the Mchinji District of Malawi were interviewed between March and December 2013. The overall utilisation of maternal healthcare was calculated by combining the use of antenatal, delivery and postnatal care into one variable-continuum of care. Univariate and multivariate logistic regressions were performed to determine the factors associated with utilisation of maternal healthcare., Results: Utilisation of maternal healthcare in the Mchinji District was inadequate; only 24% of women received the recommended package. Being further from a healthcare facility (OR = 0.2, 95%CI = 0.04-0.96), having at least one live child (OR = 0.87, 95%CI = 0.84-0.99), previous experience of miscarriage (OR = 0.64, 95%CI = 0.50-0.82) or abuse (OR = 0.81, 95%CI = 0.69-0.95) reduced utilisation, whereas being in the richest 20% (OR = 1.33 95%CI = 1.08-1.65), having a planned pregnancy (OR = 1.3, 95%CI = 1.11-1.51) or more control over decisions (OR = 1.09, 95%CI = 0.80-1.49) increased utilisation., Conclusion: Seven groups of women were identified as having an increased risk of low utilisation of maternal healthcare; women living >5km from a healthcare facility, within the poorest socio-economic group, experiencing an unplanned pregnancy, with at least one live child, experience of a previous miscarriage, no control over their healthcare decisions or experience of abuse. Policy makers should pay extra attention to these high-risk groups when designing and delivering strategies to improve maternal healthcare utilisation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Stewart, Hall. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Early pregnancy complications are common and often result in pregnancy loss, which can be emotionally challenging for women. Research on the emotional experiences of those attending Early Pregnancy Assessment Units [EPAUs] is scarce. This analysis explored the emotions which women spontaneously reported when being interviewed about their experiences of using EPAU services. Materials and methods: Semi-structured telephone interviews were conducted with a purposive sample of 38 women. Using Thematic Framework Analysis, we identified six unique emotional typologies which mapped onto women's clinical journeys. Results: Women with ongoing pregnancies were characterized as having: "Anxious Presentation" or "Sustained Anxiety due to Diagnostic Uncertainty", dependent on whether their initial scan result was inconclusive. Women with pregnancy loss had one of four emotional typologies, varying by diagnostic timing and required interventions: "Anxious-Upset"; "Anxious-Upset after Diagnostic Uncertainty"; "Anxious-Upset with Procedural Uncertainty"; "Anxious with Sustained Uncertainty". Conclusions: We provide insights into the distinct emotions associated with different clinical pathways through EPAU services. Our findings could be used to facilitate wider recognition of women's emotional journeys through early pregnancy complications and stimulate research into how best to support women and their partners, in these difficult times.

T helper 17 (Th17) cells regulate mucosal barrier defenses but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been elucidated, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation; however, it is not clear whether the closely related RORα, which is co-expressed in Th17 cells, has a distinct role. Here, we demonstrated that although dispensable for Th17 cell differentiation, RORα was necessary for optimal Th17 responses in peripheral tissues. The absence of RORα in T cells led to reductions in both RORγt expression and effector function among Th17 cells. Cooperative binding of RORα and RORγt to a previously unidentified Rorc cis-regulatory element was essential for Th17 lineage maintenance in vivo. These data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program., Competing Interests: Declaration of interests D.R.L. is a founder and serves on the SABs of Vedanta Biosciences and Immunai, Inc. He is also on the SABs of Chemocentryx, Evommune, and IMIDomics and is a director of Pfizer, Inc., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Anatomic studies have suggested that the central insular sulcus (CIS) runs in line with the Rolandic sulcus (RS). The radiographic relationship between the RS and CIS has not been systematically studied. This study aims to evaluate the applicability of using the CIS as a radiologic landmark to identify the RS., Methods: We retrospectively reviewed 100 consecutive normal magnetic resonance imaging (MRI) scans (200 hemispheres) performed at a single institution. MRI scans with any intracranial pathology or finding were excluded. Sagittal and axial fluid-attenuated inversion recovery sequences were used in this study. Two evaluators independently evaluated the relationship of the CIS and RS in all MRI scans. A predefined 3-step method was then used to identify the CIS, RS, and hand motor area in sagittal and axial images., Results: The CIS was found to be correlated with the RS in 191 hemispheres (95.5%). In the remaining 9 hemispheres, the postcentral sulcus represented the most correlated sulcus with the CIS (7 hemispheres). The interrater agreement was 0.673 (P < 0.05), indicating a substantial agreement. The hand motor area was identified in the same section as the CIS in 175 hemispheres (87.5%)., Conclusions: The CIS is a highly reliable radiographic landmark for the identification of the RS. The hand motor area can also be identified reliably using this method., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Morphological and emerging molecular studies have provided evidence for heterogeneity within the oligodendrocyte population. To address the regional and age-related heterogeneity of human mature oligodendrocytes (MOLs) we applied single-cell RNA sequencing to cells isolated from cortical/subcortical, subventricular zone brain tissue samples, and thoracolumbar spinal cord samples. Unsupervised clustering of cells identified transcriptionally distinct MOL subpopulations across regions. Spinal cord MOLs, but not microglia, exhibited cell-type-specific upregulation of immune-related markers compared to the other adult regions. SVZ MOLs showed an upregulation of select number of development-linked transcription factors compared to other regions; however, pseudotime trajectory analyses did not identify a global developmental difference. Age-related analysis of cortical/subcortical samples indicated that pediatric MOLs, especially from under age 5, retain higher expression of genes linked to development and to immune activity with pseudotime analysis favoring a distinct developmental stage. Our regional and age-related studies indicate heterogeneity of MOL populations in the human CNS that may reflect developmental and environmental influences., (© 2022 Wiley Periodicals LLC.)

Objective: To determine whether household contacts of confirmed cases of COVID-19 have an increased risk of hospitalisation or death., Methods: We used the HOSTED data set of index cases of COVID-19 in England between June and November 2020, linked to Secondary Uses Service data on hospital episodes and Office for National Statistics' mortality data. Multivariable logistic regression models of the odds of household contacts being hospitalised or dying within six weeks of an index case, adjusted for case type, age, sex and calendar month were calculated. Excess risk was determined by comparing the first six weeks after the index case with 6-12 weeks after the index case in a survival analysis framework., Results: Index cases were more likely to be hospitalised or die than either secondary cases or non-cases, having adjusted for age and sex. There was an increased risk of hospitalisation for non-cases (adjusted hazard ratio (aHR) 1.10; 95% confidence interval (CI) 1.04, 1.16) and of death (aHR 1.57; 95% CI 1.14, 2.16) in the first six weeks after an index case, compared to 6-12 weeks after., Conclusion: Risks of hospitalisation and mortality are predictably higher in cases compared to non-cases. The short-term increase in risks for non-case contacts following diagnosis of the index case may suggest incomplete case ascertainment among contacts, although this was relatively small., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a preclinical study of PDX mice. Further, we show how our DBS-based ctDNA assay can be used to detect gene-specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays could transform future trial designs in both mice and patients by enabling increased sampling and molecular monitoring., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Social displacement is the proposition that time spent on social media replaces time spent in face-to-face interaction, particularly with close friends and family, thus reducing well-being. There is clear evidence of growing mobile and social media use, and some evidence of a decline in face-to-face communication. This essay concludes, however, there is very little direct or causal evidence of social media time displacing face-to-face time. This article concludes that increasing social media use most likely displaces other media activities. To explain findings that seem to support social displacement, this essay examines the difference between population-level trends and within-individual behavior, and the difference between within-person and between-person displacement., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Multiple myeloma (MM) accounts for 1% to 2% of all cancers. Exposure to the pesticide Agent Orange (AO) has been established as a potential risk factor for the development of monoclonal gammopathy of undetermined significance (MGUS) and, subsequently, MM in Vietnam War veterans., Methods: This study explored variation in survival related to AO exposure, transformation from MGUS to MM, and covariates. Vietnam War veterans with MM or MGUS were identified in Veterans Health Administration (VHA) health records data. Cox proportional hazards models analyzed survival as a function of AO, race, ethnicity, body mass index, nicotine dependence, alcohol use disorder, Charlson Comorbidity Index, and treatment. Autologous hematopoietic cell transplantation for MM was defined by procedure codes., Results: In the VHA 16,366 patients were identified: 11,112 patients diagnosed with MGUS and 7261 with MM during fiscal years 2010 to 2015 were identified; 12% (n = 2007) had both diagnoses. No statistically significant difference in the rate of transformation from MGUS to MM in the AO exposed and AO not exposed groups was found. In survival models, AO exposure was associated with slightly lower mortality. Alcohol use disorder, nicotine dependence, older age, and greater comorbidity burden increased mortality risk. Black race, female sex, obesity/overweight, and hematopoietic cell transplantation for patients with MM were protective factors. AO exposure was associated with decreased mortality for both MM/MGUS groups. Transformation increased mortality risk for patients with MGUS and decreased mortality risk for patients with MM., Conclusions: Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and drug use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies should examine the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to best identify their disease course and optimize their care in the latter part of their life., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article., (Copyright © 2022 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Abnormalities in the expression of metabotropic glutamate receptor type 5 (mGluR5) have been observed in the hippocampus of patients with drug-resistant mesial Temporal Lobe Epilepsy (mTLE). Ex-vivo studies in mTLE hippocampal surgical specimens have shown increased mGluR5 immunoreactivity, while in vivo whole brain imaging using positron emission tomography (PET) demonstrated reduced hippocampal mGluR5 availability. To further understand mGluR5 abnormalities in mTLE, we performed a saturation autoradiography study with [ 3 H]ABP688 (a negative mGluR5 allosteric modulator). We aimed to evaluate receptor density (B max ) and dissociation constants (K D ) in hippocampal mTLE surgical specimens and in non-epilepsy hippocampi from necropsy controls. mTLE specimens showed a 43.4% reduction in receptor density compared to control hippocampi, which was independent of age, sex and K D (multiple linear regression analysis). There was no significant difference in K D between the groups, which suggests that the decreased mGluR5 availability found in vivo with PET cannot be attributed to reduced affinity between ligand and binding site. The present study supports that changes within the epileptogenic tissue include mGluR5 internalization or conformational changes that reduce [ 3 H]ABP688 binding, as previously suggested in mTLE patients studied in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zimmermann, Minuzzi, Aliaga Aliaga, Guiot, Hall, Soucy, Massarweh, El Mestikawy, Rosa-Neto and Kobayashi.)

Nanoarchitectural control of matter is crucial for next-generation technologies. DNA origami templates are harnessed to accurately position single molecules; however, direct single molecule evidence is lacking regarding how well DNA origami can control the orientation of such molecules in three-dimensional space, as well as the factors affecting control. Here, we present two strategies for controlling the polar ( θ ) and in-plane azimuthal ( ϕ ) angular orientations of cyanine Cy5 single molecules tethered on rationally-designed DNA origami templates that are physically adsorbed (physisorbed) on glass substrates. By using dipolar imaging to evaluate Cy5's orientation and super-resolution microscopy, the absolute spatial orientation of Cy5 is calculated relative to the DNA template. The sequence-dependent partial intercalation of Cy5 is discovered and supported theoretically using density functional theory and molecular dynamics simulations, and it is harnessed as our first strategy to achieve θ control for a full revolution with dispersion as small as ±4.5°. In our second strategy, ϕ control is achieved by mechanically stretching the Cy5 from its two tethers, being the dispersion ±10.3° for full stretching. These results can in principle be applied to any single molecule, expanding in this way the capabilities of DNA as a functional templating material for single-molecule orientation control. The experimental and modeling insights provided herein will help engineer similar self-assembling molecular systems based on polymers, such as RNA and proteins.

Objectives: Training in emotion management is not a standard part of medical education. This study's objective was to understand physicians' challenges navigating emotion (their own and their patients') and identify areas for intervention to support physician wellness and enhance patient care., Methods: In 2019, we surveyed 103 physicians in emergency medicine, internal medicine, family medicine, and neurology. Participants quantitatively reported emotion training, emotions that were challenging, and barriers to addressing emotion. They provided qualitative examples of emotion challenges and successes that we analyzed using an inductive thematic analysis., Results: There were no significant differences in responses by specialty. Only 10% reported receiving emotion management training, with no evidence that more recently trained physicians received more. Those who had received training on emotion reported greater comfort in dealing with patients' emotions and were more likely to engage in teaching on emotion. There were gender and career stage differences regarding which emotions physicians found most challenging. The authors identified central themes of emotion-related challenges and successes., Conclusions: Targeted educational initiatives are needed to advance physicians' ability to navigate emotion in clinical encounters., Practice Implications: Developing strategies for managing patients' emotions may better prepare physicians for navigating the emotional demands of practicing medicine., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Objectives: Accurate delineation of the seizure-onset zone (SOZ) in focal drug-resistant epilepsy often requires stereo-EEG (SEEG) recordings. Our aims were to propose a truly objective and quantitative comparison between EEG/magnetoencephalography (MEG) source imaging (EMSI), EEG/fMRI responses for similar spikes with primary irritative zone (PIZ) and SOZ defined by SEEG and to evaluate the value of EMSI and EEG/fMRI to predict postsurgical outcome., Methods: We identified patients with drug-resistant epilepsy who underwent EEG/MEG, EEG/fMRI, and subsequent SEEG at the Epilepsy Service from the Montreal Neurological Institute and Hospital. We quantified multimodal concordance within the SEEG channel space as spatial overlap with PIZ/SOZ and distances to the spike-onset, spike maximum amplitude and seizure core intracerebral channels by applying a new methodology consisting of converting EMSI results into SEEG electrical potentials (EMSIe-SEEG) and projecting the most significant fMRI response on the SEEG channels (fMRIp-SEEG). Spatial overlaps with PIZ/SOZ (AUC PIZ , AUC SOZ ) were assessed by using the area under the receiver operating characteristic curve (AUC). Here, AUC represents the probability that a randomly picked active contact exhibited higher amplitude when located inside the spatial reference than outside., Results: Seventeen patients were included. Mean spatial overlaps with the PIZ and SOZ were 0.71 and 0.65 for EMSIe-SEEG and 0.57 and 0.62 for fMRIp-SEEG. Good EMSIe-SEEG spatial overlap with the PIZ was associated with smaller distance from the maximum EMSIe-SEEG contact to the spike maximum amplitude channel (median distance 14 mm). Conversely, good fMRIp-SEEG spatial overlap with the SOZ was associated with smaller distances from the maximum fMRIp-SEEG contact to the spike-onset and seizure core channels (median distances 10 and 5 mm, respectively). Surgical outcomes were correctly predicted by EEG/MEG in 12 of 15 (80%) patients and EEG/fMRI in 6 of 11(54%) patients., Discussion: With the use of a unique quantitative approach estimating EMSI and fMRI results in the reference SEEG channel space, EEG/MEG and EEG/fMRI accurately localized the SOZ and the PIZ. Precisely, EEG/MEG more accurately localized the PIZ, whereas EEG/fMRI was more sensitive to the SOZ. Both neuroimaging techniques provide complementary localization that can help guide SEEG implantation and select good candidates for surgery., (© 2022 American Academy of Neurology.)

Study Question: Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week's gestation?, Summary Answer: Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage., What Is Known Already: Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection., Study Design, Size, Duration: This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week's gestation at the time of recruitment., Participants/materials, Setting, Methods: The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: 'presumed infected', i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; 'uncertain', i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and 'presumed uninfected', i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2., Main Results and the Role of Chance: A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7-9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8-11). Seventy-seven women were in the 'presumed infected' group (77/3041, 2.5% [95% CI 2-3]), 295/3041 were in the uncertain group (9.7% [95% CI 9-11]) and the rest in the 'presumed uninfected' (87.8%, 2669/3041 [95% CI 87-89]). The rate of early miscarriage was 14% in the 'presumed infected' group, 5% in the 'uncertain' and 8% in the 'presumed uninfected' (11/77 [95% CI 6-22] versus 15/295 [95% CI 3-8] versus 212/2669 [95% CI 7-9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the 'presumed infected' group (relative rate 1.7, 95% CI 1.0-3.0, P = 0.06)., Limitations, Reasons for Caution: We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the 'presumed uninfected' and 'uncertain' groups may have had asymptomatic infections. The number of 'presumed infected' in our study was low and therefore the study was relatively underpowered., Wider Implications of the Findings: This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection., Study Funding/competing Interest(s): This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi&#95;disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

We previously reported that feeding Se-biofortified alfalfa hay to weaned beef calves in a preconditioning program increases whole-blood Se (WB-Se) concentrations and nasal microbiome abundance and diversity during the preconditioning period, decreases morbidity and mortality during the feedlot period, and increases carcass weight and quality at slaughter. The objective of the current study was to see whether similar improvements can be achieved through Se supplementation of dams during various pregnancy trimesters. In a two-year experimental study, 80 Angus-cross cows received once-weekly Se-yeast boluses containing 105 mg of Se, during either the first (TR-1), second (TR-2), or third (TR-3) pregnancy trimester, or were not bolused (CTR). Whole-blood Se concentrations were higher from CTR, to TR-1, to TR-2, and to TR-3 in newborn calves (all p < 0.01). At weaning, only calves from TR-3 mothers had higher WB-Se concentrations compared with calves from CTR mothers (p = 0.02), and no significant differences in nasal microbiome abundance and diversity or nasal microbiota were observed. In the feedlot period, morbidity was low, and no differences were observed. At slaughter, no differences in carcass weight and quality were observed. In conclusion, Se supplementation of pregnant cows is effective for increasing WB-Se concentration of newborn calves, and the increase can be sustained until weaning for calves born to TR-3 dams. However, the increase in WB-Se concentrations is small and does not result in beneficial changes in the nasal microbiome. Thus, calves should be fed Se-biofortified forages again at weaning in a preconditioning program in order to diversify the nasal microbiome prior to entering the feedlot.